Evolution of definitive external beam radiation therapy in the treatment of prostate cancer.

PURPOSE: Although the clinical significance of a diagnosis of prostate cancer for some men is debated, for many men it leads to significant morbidity and mortality. Radical treatment of clinically localized prostate cancer has been shown to improve survival in men with intermediate or high-risk disease. There is no high level evidence to support the superiority of radical prostatectomy, with or without adjuvant or salvage external beam radiotherapy in comparison to definitive radiotherapy with or without androgen deprivation, and the choice should be individualized. External beam radiation therapy practices are in constant evolution, and numerous strategies have been investigated to improve either efficacy or reduce toxicity, or both. METHODS: Randomized controlled trials investigating strategies to improve efficacy, reduce toxicity, or both of external beam radiotherapy have been reviewed in men with prostate cancer without nodal or distant metastases. These strategies include the use of neo-adjuvant and adjuvant androgen deprivation, dose-escalation, hypofractionation, whole pelvic radiation therapy, incorporation of improved imaging, image- guided radiation therapy, and adjuvant systemic therapy. The evidence to date for these strategies is discussed, noting limitations in applying the results of reported trials to men treated in contemporary settings. RESULTS: A number of strategies have shown improvements in biochemical control using external beam radiotherapy. To date, only with the use of androgen deprivation therapy has this translated into improvements in disease specific and overall survival. This may reflect the long natural history of prostate cancer and high incidence of competing risks. Technological advances have enabled dose escalation with reduced toxicity, of paramount importance given the long natural history. RESULTS: The use of external beam radiation therapy in prostate cancer is evolving with numerous strategies incorporated to improve outcomes. The optimum dose and fractionation and use of androgen deprivation or systemic adjuvants for each man is unclear based on current evidence and prognostic and predictive parameters. Patient preferences play an important role in chosen therapy. It is hoped that future studies better capture all prostate cancer- and treatment- related morbidity to clarify the optimal therapy choices for each man with prostate cancer.

Hypofractionation for clinically localized prostate cancer.

BACKGROUND: Using hypofractionation (fewer, larger doses of daily radiation) to treat localized prostate cancer may improve convenience and resource use. For hypofractionation to be feasible, it must be at least as effective for cancer-related outcomes and have comparable toxicity and quality of life outcomes as conventionally fractionated radiation therapy. OBJECTIVES: To assess the effects of hypofractionated external beam radiation therapy compared to conventionally fractionated external beam radiation therapy for men with clinically localized prostate cancer. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid) and trials registries from 1946 to 15 March 2019 with reference checking, citation searching and contact with study authors. Searches were not limited by language or publication status. We reran all searches within three months (15th March 2019) prior to publication. SELECTION CRITERIA: Randomized controlled comparisons which included men with clinically localized prostate adenocarcinoma where hypofractionated radiation therapy (external beam radiation therapy) to the prostate using hypofractionation (greater than 2 Gy per fraction) compared with conventionally fractionated radiation therapy to the prostate delivered using standard fractionation (1.8 Gy to 2 Gy per fraction). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. Two authors independently assessed trial quality and extracted data. We used Review Manager 5 for data analysis and meta-analysis. We used the inverse variance method and random-effects model for data synthesis of time-to-event data with hazard ratios (HR) and 95% confidence intervals (CI) reported. For dichotomous data, we used the Mantel-Haenzel method and random-effects model to present risk ratios (RR) and 95% CI. We used GRADE to assess evidence quality for each outcome. MAIN RESULTS: We included 10 studies with 8278 men in our analysis comparing hypofractionation with conventional fractionation to treat prostate cancer.Primary outcomesHypofractionation may result in little or no difference in prostate cancer-specific survival [PC-SS] (HR 1.00, 95% CI 0.72 to 1.39; studies = 8, participants = 7946; median follow-up 72 months; low-certainty evidence). For men in the intermediate-risk group undergoing conventional fractionation this corresponds to 976 per 1000 men alive after 6 years and 0 more (44 fewer to 18 more) alive per 1000 men undergoing hypofractionation.We are uncertain about the effect of hypofractionation on late radiation therapy gastrointestinal (GI) toxicity (RR 1.10, 95% CI 0.68 to 1.78; studies = 4, participants = 3843; very low-certainty evidence).Hypofractionation probably results in little or no difference to late radiation therapy genitourinary (GU) toxicity (RR 1.05, 95% CI 0.93 to 1.18; studies = 4, participants = 3843; moderate-certainty evidence). This corresponds to 262 per 1000 late GU radiation therapy toxicity events with conventional fractionation and 13 more (18 fewer to 47 more) per 1000 men when undergoing hypofractionation.Secondary outcomesHypofractionation results in little or no difference in overall survival (HR 0.94, 95% CI 0.83 to 1.07; 10 studies, 8243 participants; high-certainty evidence). For men in the intermediate-risk group undergoing conventional fractionation this corresponds to 869 per 1000 men alive after 6 years and 17 fewer (54 fewer to 17 more) participants alive per 1000 men when undergoing hypofractionation.Hypofractionation may result in little to no difference in metastasis-free survival (HR 1.07, 95% CI 0.65 to 1.76; 5 studies, 4985 participants; low-certainty evidence). This corresponds to 981 men per 1000 men metastasis-free at 6 years when undergoing conventional fractionation and 5 more (58 fewer to 19 more) metastasis-free per 1000 when undergoing hypofractionation.Hypofractionation likely results in a small, possibly unimportant reduction in biochemical recurrence-free survival based on Phoenix criteria (HR 0.88, 95% CI 0.68 to 1.13; studies = 5, participants = 2889; median follow-up 90 months to 108 months; moderate-certainty evidence). In men of the intermediate-risk group, this corresponds to 804 biochemical-recurrence free men per 1000 participants at six years with conventional fractionation and 42 fewer (134 fewer to 37 more) recurrence-free men per 1000 participants with hypofractionationHypofractionation likely results in little to no difference to acute GU radiation therapy toxicity (RR 1.03, 95% CI 0.95 to 1.11; 4 studies, 4174 participants at 12 to 18 weeks' follow-up; moderate-certainty evidence). This corresponds to 360 episodes of toxicity per 1000 participants with conventional fractionation and 11 more (18 fewer to 40 more) per 1000 when undergoing hypofractionation. AUTHORS' CONCLUSIONS: These findings suggest that moderate hypofractionation (up to a fraction size of 3.4 Gy) results in similar oncologic outcomes in terms of disease-specific, metastasis-free and overall survival. There appears to be little to no increase in both acute and late toxicity.

The role of volumetric modulated arc therapy (VMAT) in gynaecological radiation therapy: A dosimetric comparison of intensity modulated radiation therapy versus VMAT.

INTRODUCTION: For gynaecological cancers, volumetric modulated arc therapy (VMAT) offers comparable plan quality with shorter treatment delivery times when compared to intensity modulated radiation therapy (IMRT). METHODS: The clinical IMRT plans of twenty gynaecological cancer patients were compared with a retrospectively generated VMAT plan. Planning target volume (PTV) metrics compared were D95 > 99%, homogeneity index, and conformity index. Organs at risk (OAR) doses compared were bladder V45 < 35%, bowel V40 < 30%, femoral head and neck (FHN) V30 < 50%, V44 < 35% and V44 < 5%. Plan quality was also assessed by comparing the monitor units (MU), treatment time and the patient-specific quality assurance results. RESULTS: VMAT and IMRT resulted in comparable PTV coverage with D95 values of 98.92% ± 0.69% and 98.91% ± 1.43% respectively, and homogeneity index values of 0.08 ± 0.02 (VMAT) and 0.08 ± 0.03 (IMRT). The conformity index for VMAT was 0.93 ± 0.04 and IMRT 0.85 ± 0.06 (P < 0.001). For the bowel tolerance (40 Gy < 30%) VMAT resulted in 22.39% ± 12.5% compared to 28.8% ± 16.78% for IMRT, with bladder and FHN VMAT doses also lower. VMAT MU were 694.35 ± 126.56 compared to 606.8 ± 96.16 for IMRT (P < 0.01). Treatment times of 6.6 ± 0.82 min and 2.47 ± 0.35 min were achieved for IMRT and VMAT respectively. CONCLUSION: VMAT showed improvements in sparing OAR compared to IMRT. Target volume coverage with VMAT was equivalent or better than that of IMRT. These results in conjunction with the confirmed shorter treatment delivery time, have led to the development and implementation of a clinical protocol.

Adjuvant radiotherapy following radical prostatectomy for prostate cancer.

BACKGROUND: Men who have a radical prostatectomy (RP) for prostate cancer that does not involve lymph nodes, but extends beyond the prostate capsule into the seminal vesicles or to surgical margins, are at increased risk of relapse. In men with these high risk factors, radiotherapy (RT) directed at the prostate bed after surgery may reduce this risk, and be curative. OBJECTIVES: To evaluate the effect of adjuvant RT following RP for prostate cancer in men with high risk features compared with RP. SEARCH METHODS: We searched the Cochrane Prostatic Diseases and Urological Cancers Specialised Register (23 February 2011), the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE (January 1966 to February 2011), PDQ® (Physician Data Query) trial registry databases for ongoing studies (2 November 2010), reference lists from selected studies and reviews, and handsearched relevant conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCT) comparing RP followed by RT with RP alone. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the studies for inclusion and bias and extracted data for analysis. Authors were contacted to clarify data and obtain missing information. MAIN RESULTS: We found three RCTs involving 1815 men. Adjuvant RT following prostatectomy did not affect overall survival at 5 years (RD (risk difference) 0.00; 95% CI -0.03 to 0.03), but improved survival at 10 years (RD -0.11; 95% CI -0.20 to -0.02). Adjuvant RT did not improve prostate cancer-specific mortality at 5 years (RD -0.01; 95% CI -0.03 to 0.00). Adjuvant RT did not reduce metastatic disease at 5 years (RD -0.00; 95% CI -0.04 to 0.03), but reduced it at 10 years (RD -0.11; 95% CI -0.20 to -0.01). It improved local control at 5 and 10 years (RD -0.10; 95% CI -0.13 to -0.06 and RD -0.14; 95% CI -0.21 to -0.07, respectively), and biochemical progression-free survival at 5 years and 10 years (RD -0.16; 95% CI -0.21 to -0.11 and RD -0.29; 95% CI -0.39 to -0.19, respectively). There were no data for clinical disease-free survival. Adjuvant RT increased acute and late gastrointestinal toxicity [do you have the rd for this?], urinary stricture (RD 0.05; 95% CI 0.01 to 0.09) and incontinence (RD 0.04; 95% CI 0.01 to 0.08). It did not increase erectile dysfunction or degrade quality of life (RD 0.01; 95% CI -0.06 to -0.26), but with limited data. AUTHORS' CONCLUSIONS: Adjuvant RT after RP improves overall survival and reduces the rate of distant metastases, but these effects are only evident with longer follow up. At 5 and 10 years it improves local control and reduces the risk of biochemical failure, although the latter is not a clinical endpoint. Moderate or severe acute and late toxicity is minimal. There is an increased risk of urinary stricture and incontinence, but no detriment to quality of life, based on limited data. Given that the majority of men who have undergone a RP have a longer life expectancy, radiotherapy should be considered for those with high-risk features following radical prostatectomy. The optimal timing is unclear.

The effect of anaemia on efficacy and normal tissue toxicity following radiotherapy for locally advanced squamous cell carcinoma of the head and neck.

PURPOSE: The aims of this analysis were to determine the effect of anaemia on loco-regional control, relapse-free survival, cause-specific survival, overall survival, and acute and late radiation therapy toxicity in patients with Stage III and IV squamous cell carcinoma of the head and neck treated with radiotherapy. PATIENTS AND METHODS: Between 1991 and 1998, 350 patients were randomly assigned to either conventional radiotherapy, (70 Gy in 35 fractions in 49 days) or to accelerated radiotherapy (59.4 Gy in 33 fractions in 24 days). Patients were divided into two groups according to their haemoglobin level: a normal haemoglobin group (>/=13 g/dl in males, >/=12 g/dl in females) and a low haemoglobin group (<13 g/dl in males, <12 g/dl in females). The influence of anaemia on cause-specific survival and the development of confluent mucositis independent of other variables was tested using Cox proportional hazards model. RESULTS: Of 350 patients recruited to the trial, 238 had haemoglobin measurements and were eligible for inclusion in this secondary analysis. One hundred and ninety-three were considered to have normal haemoglobin, and 45 patients were considered to be anaemic. There were significant differences between the groups in loco-regional control, relapse-free survival, cause-specific survival and overall survival, with hazards ratios of 0.56 (95% confidence interval (CI) 0.34-0.94), 0.57 (95% CI 0.35-0.92), 0.49 (95% CI 0.29-0.85) and 0.43 (95% CI 0.26-0.70) in favour of the normal haemoglobin group. Using Cox proportional hazards modelling, haemoglobin level was a significant predictor of cause-specific survival in addition to disease site, stage, and Eastern Cooperative Oncology Group status. There were no statistically significant differences between the groups in the development of acute or late reactions. CONCLUSION: Significant reductions in loco-regional control, disease-free survival, cause-specific survival and overall survival occur in the presence of anaemia. No significant differences in normal tissue toxicity have been identified in this analysis.